5-HT1F receptor agonism as a novel therapeutic strategy following spinal cord injury

点击翻译按钮获取中文摘要

The goal of this project is to study the 5-hydroxytryptamine 1F (5-HT1F) in stimulating mitochondrial biogenesis (MB) and recovery from spinal cord injury (SCI). SCI is a devastating disorder often resulting in loss of function below the injury site. While combat-related spinal trauma has been documented for centuries, in recent years, service members have been threatened by more advanced warfare, such as rocket-propelled grenades and improvised explosive devices, ultimately inducing more severe and complex injuries, including SCI. Further, and importantly, advancements in personal protection, vehicular protection and medical capabilities have allowed current military personnel to survive injuries that would have proven lethal in the past. The devastating and debilitating nature of these injuries, however, including SCI, has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing care for 25% of total victims in the United States. The development of pharmacological therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the military healthcare system. SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Neuronal loss of mitochondrial function ultimately leads to excitotoxicity and oxidative stress, emphasizing the critical nature of restoration of mitochondrial function following SCI. Evidence suggests that restoration of mitochondrial function after injury could protect against further injury progression and enhance recovery. Studies investigating mitochondria as a therapeutic target for SCI have only addressed individual aspects of mitochondrial function and have proven largely inefficacious. Therapeutics pursuing reestablishment of mitochondrial homeostasis through increased MB, however, following SCI could alleviate multiple facets of injury progression. Our preliminary data indicate that the 5-HT1F agonism induces MB in the spinal cord of both naïve mice and following SCI. Additionally, mice treated daily with the agonist LY344864 following SCI exhibited improved mitochondrial homeostasis, as well as decreased lesion volume, and increased vascular and locomotor activity by 7 days post-injury. Remarkably, LY344864 efficacy was similar when administration was initiated 1 or 8 h post-SCI. This effect was not observed in mice lacking the 5-HT1F receptor, indicating that the presence of this receptor is necessary for LY344864-induced MB. Lasmiditan is a potent and specific 5-HT1F receptor agonist that is undergoing phase III clinical trials for migraine headaches. Treatment with lasmiditan beginning 1 h post-SCI also induced MB and improved recovery. We hypothesize that treatment with LY344864/lasmiditan following SCI will increase MB, resulting in improved locomotor recovery and pain response, decreased neuronal death/dysfunction and increased vascular repair post-SCI. We propose the following Specific Aims: 1) Determine MB, mitochondrial homeostasis (e.g. fission/fusion) and function, locomotor capability and pain in response to LY344864/lasmiditan treatment post-SCI in female and male mice; 2) Elucidate lesion volume, oxidative damage, and neuronal apoptosis in response to LY344864/lasmiditan post-SCI in female and male mice and 3) Determine vascular recovery and blood-spinal cord barrier (BSCB) integrity in response to LY344864/lasmiditan post-SCI in female and male mice Successful completion of these studies could unveil 5-HT1F receptor-mediated MB as a potential strategy for therapeutic treatment of SCI. Additionally, the proposed study will use a novel target, 5-HT1F receptor agonism, and lasmiditan, which is undergoing clinical trials and has the potential to be repurposed for the treatment of SCI. Finally, these studies will initiate drug administration 8 h after injury and be performed in both male and female mice, strengthening clinical applicability.